Recent surveys in the U.S. reveal that about 2.6 million individuals reported use of cocaine/crack in the past month. Despite a concerted research effort to develop an effective pharmacotherapy, no broadly effective therapies have been discovered. Cocaine exerts its reinforcing effects largely through interactions with central dopamine pathways, and chronic use of cocaine leads to dysregulation of these neural systems. This application proposes to examine a novel agent, aripiprazole (Abilify(r)), for its potential efficacy against cocaine by employing well-controlled experimental methods in a human laboratory setting. Aripiprazole is the newest atypical antipsychotic marketed in the U.S.; its neuropharmacological profile is truly unique and sets it apart from all other atypical neuroleptics. Aripiprazole has a high affinity for D2 and 5-HT1a receptors where it acts as a partial agonist, and at 5-HT2 receptors where it acts as an antagonist. We hypothesize that aripiprazole may both block the synaptic effects of cocaine and improve the neural perturbations resulting from chronic cocaine use. Healthy, adult, cocaine-dependent volunteers (n=36) who also smoke cigarettes will be enrolled as inpatients for 45 days. Following a brief wash-out and single-blind placebo lead-in, they will be randomly assigned to 1 of 3 treatment groups (0,15 or 30 mg aripiprazole p.o/day) under double-blind conditions. Cocaine challenge sessions will be conducted during the placebo lead-in, acute dosing phase, and at steady-state. During each phase, the direct pharmacodynamic and pharmacokinetic interaction between cocaine and aripiprazole will be examined in cocaine dose-effect challenge sessions. The effects of aripiprazole treatment on the reinforcing effects of cocaine will be examined directly with a self-administration procedure that employs alternative reinforcers and has been well-characterized by our laboratory. Cocaine will be examined over a range of doses relevant to those used illicitly, and pharmacodynamic assessments will be multi-dimensional, including subjective, objective, physiological and behavioral outcomes. In addition, because preliminary data suggest that atypical antipsychotics may reduce cigarette smoking, a secondary aim is to examine directly the effects of aripiprazole on smoking behavior in comparison to placebo. This study provides a unique opportunity to examine smoking under controlled conditions during a period of confinement; both smoking topography procedures and naturalistic smoking measures will be employed. Overall, this project will explore the potential therapeutic efficacy of a novel agent, aripiprazole, for the treatment of cocaine dependence while simultaneously providing the requisite safety data needed to launch an outpatient clinical trial and exploring the potential efficacy of this agent for smoking reduction or cessation. [unreadable] [unreadable]